Project Summary/Abstract The current proposal requests support for a mentored career development award for Dr. Matthew Karafin, a junior faculty member in transfusion medicine. Dr. Karafin's long-term goal is to be an independently-funded clinical scientist in transfusion medicine with a focus on sickle cell disease (SCD). In this proposal, a structured career development plan, which includes focused didactic and laboratory experiences, complements three aims to address a critical question: whether older red cell units are harmful to an adult with SCD. Little is known about how the biochemical changes associated with prolonged red cell storage (the ?storage lesion?) impact patients with SCD.1 While randomized trials in other patient populations have not associated older units with adverse clinical outcomes,2-6 adults with SCD have a unique pathophysiology and may be susceptible to an older unit's altered biology. Murine models suggest that a bolus of older stored red cells, which have increased levels of surface phosphotidlyethanolamine (PE), phosphatidylserine (PS), and increased concentrations of microparticles,7-10 overwhelms macrophages and results in marked increases in inflammation and non-transferrin bound iron (NTBI), which facilitates increased virulence of microbial pathogens and fatal sepsis.11-13 To address this knowledge gap, we have conducted a series of preliminary studies in adults with SCD that demonstrated: 1) there is equipoise among blood bank directors about the effects of older units in adults with SCD,14 2) greater than 25% of adults with SCD at our own institution are predominantly transfused with older red cell units (?33 days),15,16 3) red cell surface exposure of PE and PS, and microparticle concentration, increases 20-fold, 6-fold and 4-fold from 7 to 35 days of storage, respectively,10 4) transfusion of red cell units stored ?14 days is associated with significant CD62L+ activation of macrophages in adults with SCD, and 5) in adults with SCD, receipt of older units is associated with an increased risk for infection that requires a hospital admission.15 Since storage changes, such as PS exposure, promote phagocytosis of red cells by macrophages,17-19 we hypothesize that older red cell units trigger phagocytosis and activation of circulating macrophages with a downstream immunomodulatory cascade and release of excess NTBI that leads to increased rates of infection in adults with SCD. To test this hypothesis, we will perform a randomized prospective clinical trial. In aim 1, we will determine the biochemical differences between ?30 day-old versus ?10 day-old units. In aim 2, we will determine the physiologic effects of the transfused blood in a patient with SCD. Lastly, in aim 3, we will explore the clinical implications of receiving older red cells over a 3 month period.